Oral Cannabinoid Formulations

ABSTRACT

Oral cannabinoid formulations, including an aqueous-based oral dronabinol solution, that are stable at room or refrigerated temperatures and may possess improved in vivo absorption profiles with faster onset and lower inter-subject variability.

FIELD OF INVENTION

The present invention relates to an aqueous-based oral cannabinoidsolution comprising water, alcohol and propylene glycol that is stableat room or refrigerated temperatures and has an improved in vivoabsorption profile with faster onset and lower inter-subject variabilitywhen compared with current gelatin capsule cannabinoid formulations.

BACKGROUND OF THE INVENTION

Delta-9-Tetrahydrocannabinol (also known as THC, dronabinol and D9THC)is a naturally occurring compound and is the primary active ingredientin the controlled substance marijuana. Marijuana refers to the driedflowers and leaves of Cannabis sativa, the hemp plant. These parts ofthe plant contain several compounds called cannabinoids (includingdronabinol), that may help patients with certain disease conditions.Dronabinol has been approved by the Food and Drug Administration (FDA)for the control of nausea and vomiting associated with chemotherapy and,more recently, for appetite stimulation of AIDS patients suffering fromwasting syndrome. Synthetic dronabinol has been utilized as apharmaceutically active ingredient, and Cannabis-based medicines usingbotanical sources of Cannabis rather than synthetic THC are also knownin the art.

Despite all of the work on cannabinoids and dronabinol outlined aboveand elsewhere, to date a solution formulation of a cannabinoid, such asan aqueous-based oral dronabinol solution, has not been achieved that isstable at room or refrigerated temperatures and that has an improved invivo absorption profile with faster onset and lower inter-subjectvariability than currently available dronabinol gelatin capsules.

SUMMARY OF THE INVENTION

The present invention is directed to liquid cannabinoid formulations,and more particularly to an aqueous-based oral cannabinoid solutioncomprising water, alcohol and propylene glycol that is stable at room orrefrigerated temperatures and possesses an improved in vivo absorptionprofile, with lower inter-subject variability, over existing oralcannabinoid formulations.

In one embodiment, the present invention is directed to a stable oralpharmaceutical solution comprising from about 0.1% to about 5% w/w ofdronabinol, 33% w/w or less water, from about 15 to about 95% w/walcohol, preferably from about 15 to about 65% w/w or from about 40 toabout 95% w/w and from about 5 to about 21% w/w of a co-solventconsisting of propylene glycol, polyethylene glycol or a mixture thereofand an antioxidant.

In certain embodiments, the provided formulations contain dronabinol atconcentrations of 0.05-20 mg/mL, alcohol, water, a co-solvent and anantioxidant wherein an 4.25 mg dose of dronabinol provides apharmacokinetic profile of C_(max) of 1.95±1.28 (ng/mL), AUC (0-t) of3.53±1.87 (h*ng/mL) or a T_(max) of 0.50-4.00 (h).

In other embodiments, the provided formulations contain dronabinol atconcentrations of 0.05-20 mg/mL, alcohol, water, a co-solvent and anantioxidant wherein an 4.25 mg dose of dronabinol provides apharmacokinetic profile of C_(max) of 1.95±1.28 (ng/mL), AUC (0-t) of3.53±1.87 (h*ng/mL) and a T_(max) of 0.50-4.00 (h).

In other embodiments, the provided formulations contain dronabinol atconcentrations of 0.05-20 mg/mL, alcohol, water, a co-solvent and anantioxidant wherein an 4.25 mg dose of dronabinol provides a time tofirst measurable concentration of 0.15±0.07 (h).

In certain embodiments, the provided formulations contain dronabinol atconcentrations of 0.05-20 mg/mL, alcohol, water, a co-solvent and anantioxidant wherein an an 5 mg dose of dronabinol provides apharmacokinetic profile of C_(max) of 2.4±1.30 (ng/mL), AUC (0-t) of4.23±1.97 (h*ng/mL) or a T_(max) of 0.25-4.00 (h).

In other embodiments, the provided formulations contain dronabinol atconcentrations of 0.05-20 mg/mL, alcohol, water, a co-solvent and anantioxidant wherein an an 5 mg dose of dronabinol provides apharmacokinetic profile of C_(max) of 2.4±1.30 (ng/mL), AUC (0-t) of4.23±1.97 (h*ng/mL) and a T_(max) of 0.25-4.00 (h).

All percentages of ingredients reported herein are expressed as weightby weight, unless otherwise indicated.

It is a further object of the invention to provide formulationscomprising a cannabinoid, preferably, dronabinol, and the followingingredients: (i) from about 0 to about 40% water, (ii) from about 15 toabout 65% alcohol, preferably ethanol, and (iii) a co-solvent that is(a) propylene glycol from about 0% to about 50%, (b) polyethylene glycolfrom about 0 to about 50%, and/or (c) a combination of (a) and (b), thesolution having a combined total of 100%, wherein the formulations aresuitable for oral administration and have in vivo absorption variabilityof less than 50%.

In other embodiments, the provided formulations contain 33% or lesswater, from about 0.1% to about 33% water, between about 25% to about33% w/w water; more preferably, between about 30% and about 33% w/wwater.

In yet other embodiments, the provided formulations contain about 50%w/w alcohol.

In yet other embodiments, the provided formulations contain betweenabout 5% to about 21% w/w a co-solvent.

In yet other embodiments, the provided formulations contain betweenabout 0.1% to about 5% w/w dronabinol.

In yet other embodiments, the provided formulations contain about 5.5%w/w propylene glycol and about 12% w/w polyethylene glycol.

In other embodiments, the provided formulations further includebutylated hydroxyanisole (BHA) in amount of about 0.01% w/w.

In all embodiments, the combined total of all ingredients is 100%.

In a preferred embodiment, the invention provides an oral pharmaceuticalsolution comprising about 0.54% w/w dronabinol, about 31.9% w/w water,about 12% w/w polyethylene glycol, about 5.5% w/w propylene glycol,about 0.01% w/w BHA, about 0.05% w/w sucralose, and about 50% w/walcohol.

It is a still further object of the invention to provide methods oftreatment wherein the cannabinoid formulations are suitable foradministration by the delivery route selected from the group consistingof: intrapulmonary, oral, transmucosal (eg. buccal and sublingual),transdermal, intravenous and ophthalmic.

In certain preferred embodiments, the present invention provides anaqueous cannabinoid formulation (e.g., dronabinol) that is stable at allconditions-refrigerated, cool and room temperature. In other words, incertain preferred embodiments, the stabilized aqueous cannabinoidformulations may be stored at ambient temperature and humidity, or in arefrigerator, by the patient.

In certain embodiments, formulations and methods of the inventionprovide for the active pharmaceutical cannabinoid ingredient remainingwithin at least about 90 to about 110 percent of its original amountincluded in the dosage form for at least 1 year, and preferably for atleast about 18 months after manufacture.

In certain embodiments, the cannabinoid formulations of the inventioncomprise effective amounts of one or more stabilizers to promotestability of the cannabinoid against unacceptable degradation. Thestabilizers may comprise one or more anti-oxidants, one or more organicbases, and/or other stabilizers for cannabinoids known to those skilledin the art. In certain preferred embodiments, the stabilizer comprisesbutylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) or anycombination thereof.

The invention is further directed in part to a method for stabilizing adosage form containing a cannabinoid as the active pharmaceuticalingredient, comprising dissolving a therapeutically effective amount ofthe cannabinoid in a mixture of aqueous and organic carriers. In certainembodiments, the carrier comprises buffering agents. In certainembodiments, the carrier further comprises one or more stabilizers forthe cannabinoid (e.g, anti-oxidants, organic bases, or both, as setforth more specifically herein).

In certain embodiments, the carrier further contains an effective amountof a viscosity modifier that may be included to provide apharmaceutically acceptable viscosity to the cannabinoid dispersed inthe carrier.

In certain preferred embodiments where the stabilizer comprises anorganic base, the dosage form may comprise from about 0.001% w/w toabout 5% organic base, preferably from about 0.001% w/w to about 0.5%w/w organic base, by volume. In certain preferred embodiments, theorganic base is selected from the group consisting of butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid,sodium ascorbate, ascorbyl palmitate and any combination of theforegoing.

The anti-oxidant included in the formulations of the invention mayfurther be selected from e.g., propyl gallate, lecithin, Vitamin Etocopherol, sesamin, sesamol, sesamolin, alpha tocopherol, ascorbicacid, ascorbyl palmitate, fumaric acid, malic acid, and sodiummetabisulphite, disodium ethylenediaminetetracetic acid (EDTA), andcombinations of any of the foregoing.

The formulations of the present invention comprise a cannabinoidconcentration range of from about 0.01 to about 20 mg/ml. In certainembodiments, the formulations of the invention comprise a cannabinoid ina concentration from about 1 to about 10 mg/ml. In certain otherembodiments, the formulations of the present invention comprise acannabinoid in a formulation of about 5 mg/ml.

In certain preferred embodiments, the dosage forms of the inventioncomprises from about 0.05% to about 90% cannabinoid, preferably fromabout 0.1% to about 50% cannabinoid, more preferably about 0.1 to about10% w/w cannabinoid, and most preferably from about 0.1% to about 5%cannabinoid, by weight.

In accordance with any of the above objects, it is a further object ofthe invention to provide stabilized cannabinoid formulations where, thecarrier is buffered to a pH of from about 5 to about 10. In certainother embodiments, the carrier is buffered to a pH of from about 6 toabout 8. In accordance with any of the above objects, the formulationsof the invention are preferably buffered to a pH of from about 6.5 toabout 7.5.

In certain embodiments wherein the formulation is a solution for oraladministration, the mixture preferably contains from about 15% to about65% w/w ethanol, from about 0% to about 40% w/w water, from about 5 toabout 50% propylene glycol and from about 0% to about 50% polyethyleneglycol (PEG400). In certain preferred embodiments the aqueous-based oralsolution dronabinol formulations also contain a pharmaceuticallyacceptable sweetener such as sucralose, sucrose, sorbitol and fructosein an amount from about 0.05% to about 10% by weight.

The formulations in accordance with any of the above objects may alsoinclude sweeteners such as xylitol from about 5% to about 25%; saccharinfrom about 0.01% to about 5%; and saccharin sodium from about 0.01% toabout 5% by weight of the formulation.

The invention is further directed to a dosage form which furthercomprises one or more additional therapeutically active agents.Non-limiting examples of such additional therapeutically active agentsinclude a narcotic analgesic, a non-narcotic analgesic, an antiemetic, asteroid, and mixtures of any of the foregoing.

In certain embodiments, formulations of the invention include furtherpharmaceutically acceptable excipients. Non-limiting examples of suchpharmaceutically acceptable excipients include solubilizers for saidcannabinoid, emulsifiers, absorption enhancers, surfactants,propellants, etc.

For purposes of the present invention the terms droplets and particlesmay be used interchangeably.

The term “pharmaceutically acceptable” is defined for purposes of theinvention as meaning that a particular ingredient (e.g., pharmaceuticalcarrier, excipient) is not biologically or otherwise undesirable in anoral dosage form, i.e., the amount of the compound in an orallyadministered composition or dosage form does not cause any undesirableeffects to the formulation or to the patient.

Testing for stability may be conducted, (e.g., for eighteen monthsstability determination) by placing the dosage forms of the presentinvention under storage conditions selected from the group consisting of(i) 2-8° C., (ii) 25° C./60% relative humidity (RH) for 6-24 months;(iii) 30° C./65% relative humidity (RH) for 6-12 months; (iv) 40° C./75%relative humidity (RH) for 3-6 months; and (v) any combination thereof.

The phrase “does not degrade to an unacceptable extent” and the term“stable” as it applies to the cannabinoid formulations of the inventionis meant for purposes of the invention to mean that the formulationcontains at least about 80% w/w, and preferably at least about 90% w/wof the cannabinoid in undegraded form after exposure of the formulationto storage conditions selected from the group consisting of (i) 2-8° C.,(ii) 25° C./60% RH for 6-24 months; (iii) 30° C./65% RH for 6-12 months;(iv) 40° C./75% RH for 3-6 months; and (v) any combination thereof. Inpreferred embodiments, the phrase “does not degrade to an unacceptableextent” means that the active pharmaceutically acceptable cannabinoidingredient (e.g., dronabinol) contained within the dosage form ismaintained preferably between 90-110% of its initial (incorporated)amount during the desired (e.g., labeled) shelf-life of the dosage form(e.g., a minimum of 18 months after the date of manufacture of thedosage form).

For purposes of the invention, the term “dispersed” as it is used todescribe the presence of the cannabinoid in the pharmaceuticallyacceptable carrier, is meant to encompass a mixture of the cannabinoidand the pharmaceutically acceptable carrier in which the cannabinoid iscompletely or partially dissolved therein, or the cannabinoid ispartially or completely in solid particulate form therein.

For purposes of the invention, the term “unacceptable degradation” meansdegradation of the cannabinoid within the dosage form to an extent whichwill cause the dosage form to have cannabinoid in the dosage form at alevel outside the acceptable ranges set forth herein, and/or which causethe formulation to include cannabinoid degradants at levels which exceedthe amounts specified herein, and/or which cause the formulation to notmeet its label claim for shelf life. In certain preferred embodiments,the cannabinoid formulations of the invention are deemed stable as perthe FDA guidance for at least 18-months expiration dating.

For purposes of the present invention, the term “Cmax” means maximumplasma concentration. The term “Tmax” means the time to reach themaximum concentration and “AUC” means area under the curve.

For the purposes of the present invention, it shall be understood thatwhenever a reference is made to a pharmacokinetic value (e.g., meanCmax, median Tmax, mean AUC, etc.), that value is considered toencompass values that would provide a bioequivalent result as determinedby a regulatory authority such as the U.S. Food and Drug Administration.

In accordance with any of the above objects, the invention is alsodirected to a formulation that provides more consistent in vivoabsorption, more convenient dosing and/or improved dose flexibility ascompared to a soft gelatin dronabinol capsule formulation.

In accordance with any of the above objects, the invention is furtherdirected to a formulation that is physically stable at room orrefrigerated temperatures. In still other embodiments, the formulationsare chemically stable at room or refrigerated temperatures.

DETAILED DESCRIPTION

Lipophilic compounds that are unstable in the presence of oxygen andmoisture, such as cannabinoids, have proven difficult to formulate intostable aqueous-based formulations due to degradation and insolubility.It has been reported that when the water content of liquid dronabinolformulations increases and the amount of organic solvent such as ethanoldecreases, the drug readily falls out of solution, thus inducinginstability (Dedhiya et al., 2004).

The instability of prior art soft gelatin capsule dronabinolformulations has been overcome by virtue of the present invention whichalso has an improved in vivo absorption profile. In certain embodiments,the present invention (i) provides methods and formulations whichprovide formulations having an aqueous-based component, but that arenonetheless stable; (ii) provides methods and formulations which includeanti-oxidants and/or preservatives in effective amounts to substantiallyprevent or slow the degradation and physical instability of thedronabinol or cannabinoid in the formulation; (iii) provides methods andformulations which enhance the in vivo absorption profile of dronabinolover soft gelatin capsule dronabinol formulations; (iv) provides methodsand formulations with more convenient dosing and/or improved doseflexibility; (v) provides methods and formulations with faster onset ofdronabinol in vivo absorption and lower inter-subject variability ofplasma THC levels; (vi) provides methods and formulations withdronabinol that have an equivalent or better safety profile than softgelatin capsule dronabinol formulations; or any combination of (i)-(vi)above.

Cannabinoids

Although certain sections of this specification provide specific focuson dronabinol, one skilled in the art will appreciate that the presentinvention is applicable to the class of pharmaceutically acceptablecannabinoids. For purposes of the present invention, the term“cannabinoid” includes naturally occurring and non-natural derivativesof cannabinoids which can be obtained by derivation of naturalcannabinoids and which are unstable like natural cannabinoids. In otherwords, the cannabinoid used in the formulations of the invention may benatural, semi-synthetic, or synthetic. The cannabinoid may be includedin its free form, or in the form of a salt; an acid addition salt of anester; an amide; an enantiomer; an isomer; a tautomer; a prodrug; aderivative of an active agent of the present invention; differentisomeric forms (for example, enantiomers and diastereoisomers), both inpure form and in admixture, including racemic mixtures; enol forms. Theterm “cannabinoid” is also meant to encompass derivatives that areproduced from another compound of similar structure by the replacementof, e.g., substitution of one atom, molecule or group by another such as11-hydroxy-delta-8-tetrahydrocannabinol and11-hydroxy-delta-9-tetrahydrocannabinol. The term “cannabinoid”, as usedin the present invention, further includes delta-8-tetrahydrocannabinol,delta-9-tetrahydrocannabinol, cannabidiol, cannabinol, cannabigerol,nabilone, delta-9-tetrahydro cannabinotic acid, the non-psychotropiccannabinoid 3-dimethylnepty 11 carboxylic acid homologine 8. (J. Med.Chem. 35, 3135, 1992). The term cannabinoid also includes prodrugs ofcannabinoids, as well as pharmaceutically acceptable salts and complexesof cannabinoids. An example of a suitable prodrug is THC-hemisuccinate.

The term “cannabinoid” is further meant to encompass naturalcannabinoids that have been purified or modified, and syntheticallyderived cannabinoids, for example, United States Patent ApplicationPublication 2005/0266108, hereby incorporated by reference in itsentirety, describes a method of purifying cannabinoids obtained fromplant material. The term cannabinoid is also meant to include thecompounds described in U.S. Pat. No. 6,713,048, including levonantradol,(−)-HU-210, Win 55212-2, Anandamide, Methandamide, CP 55940, O-1057, SR141716A, etc. The disclosure of this patent is hereby incorporated byreference in its entirety.

In certain preferred embodiments of the present invention, the activeingredient (cannabinoid) comprises or consists essentially ofDelta-9-tetrahydrocannabinol, also known as (and referred to herein as)dronabinol. Dronabinol is naturally-occurring and has been extractedfrom Cannabis sativa L. (marijuana). It has also been producedchemically as described in U.S. Pat. No. 3,668,224. Dronabinol is alight-yellow resinous oil that is sticky at room temperature, buthardens upon refrigeration. It turns to a flowable liquid when heated athigher temperatures. Dronabinol is insoluble in water. It has a pKa of10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7.Dronabinol is available in natural (extracted from plant) and syntheticforms. On the other hand, synthetic dronabinol may be utilized and maybe synthesized using the starting materials Olivetol andp-2,8-menthadien-2-ol (PMD).

The term “dronabinol” is further meant to encompass naturally occurringdronabinol, metabolites, synthetically derived dronabinol, andsynthetically modified dronabinol starting with a molecule obtained froma natural source for example, United States Patent ApplicationPublication 2005/0171361, hereby incorporated by reference in itsentirety, describes a method of extracting delta-9-THC acid from theplant material by chromatography and then synthetically converting it todronabinol.

In certain preferred embodiments of the invention, the cannabinoid usedin the formulation is esterified. Esterified forms of THC are describedin U.S. Pat. No. 4,933,368 and in U.S. Pat. No. 5,389,375. Other usefulpolar esters are the hemi-ester of malonic acid and the alaninate esterof alanine. It has been reported, e.g., in U.S. Pat. Nos. 5,508,051 and5,389,375, that salts of the terminal carboxylic acid group of theester, for example, the N-methyl glutamine salt as well as the sodiumand potassium salts are also useful. The descriptions of U.S. Pat. Nos.4,933,368; 5,508,037; and 5,389,375, are incorporated herein byreference. These ester compounds are hydrolyzed in the blood streamreleasing THC to provide a high degree of bioavailability of THC withoutregard to patient conditions and anomalies.

Oral THC is known to possess erratic in vivo absorption from thegastrointestinal tract, is subject to the first-pass effect resulting inheavy metabolism with production of high levels of 11-OH-delta-9-THC. Itis reported that this 11-hydroxy metabolite is more potent agonist thandelta-9-THC. The pro-drug THC hemisuccinate (THC-HS) has been formulatedin a suppository base in order to avoid this problem, as described inU.S. Pat. Nos. 5,508,037 and 5,389,375, both of which are herebyincorporated by reference.

THC obtained by any means can be esterified by the reaction of THC withan organic acid, an organic acid halide or preferably organic acidanhydride in the presence of 4-amino-substituted pyridine alone or inadmixture with an organic amine, or in any other manner known to thoseskilled in the art. U.S. Pat. No. 6,008,383 (Elsohly, et al.), herebyincorporated by reference, describes a process for converting dronabinolto a variety of ester analogs, which process is said to be economicaland efficient. Therein, dronabinol is esterified by reaction with acarboxylic acid, an acid halide or an acid anhydride in the presence ofa 4-aminopyridine either alone or in admixture with an organic aminesuch as a mono-, di-, or tri-alkyl amine.

In certain exemplary embodiments, the cannabinoid comprises dronabinolhemisuccinate ester (THC-HS).

Formulations

Cannabinoids in general, and dronabinol specifically, are insoluble inwater. The formulations of the present invention, therefore, preferablyinclude one or more pharmaceutically acceptable co-solvents for thecannabinoid. The organic co-solvent will be present in an amounteffective to have the cannabinoids substantially solubilized in theformulation. Therefore, the amount of organic solvent in the formulationwill vary based on the concentration of the cannabinoid. The amount oforganic co-solvent will also vary based on the partition coefficient ofthe particular cannabinoid molecule.

Solvents/Co-Solvents

In certain embodiments, the solvents are organic solvents such asdehydrated alcohol, ethanol, propanol, isopropanol, propylene glycol,polyethylene glycol, and combinations thereof that are pharmaceuticallyacceptable based on the desired formulation. For purposes of thisinvention, the term “dehydrated alcohol” is used interchangeably withthe term “absolute alcohol”. The amount of dehydrated alcohol in aparticular formulation will vary based on the intended formulation andthe solubility of the cannabinoid. The amount of dehydrated alcohol inthe formulations of the present invention can range from about 10% toabout 90%; from about 15% to about 65%; and about 15% to about 50% byweight.

In certain preferred embodiments, polyethylene glycol is used as aportion of the co-solvent for the cannabinoid, more preferably a lowmolecular weight polyethylene glycol is used, most preferablypolyethylene glycol (PEG) 400.

In certain embodiments, the polyethylene glycol comprises from about 0%to about 50% by weight of the oral aqueous-based dronabinol formulationand preferably from about 0% to about 15% by weight of the oralaqueous-based dronabinol formulation.

In certain embodiments, the formulation contains another co-solvent fromabout 0% to about 50% by weight propylene glycol and preferably fromabout 1% to about 10% by weight propylene glycol. Most preferably, thesolvent and co-solvents will range from a total of about 66-74% byweight.

Solubilizing Agents

In certain embodiments of the invention further solubilizing agents areincluded in the formulation. Exemplary solubilizing agents includeCapryol 90; Cremophor RH40; Labrafil M 1944 CS; Labrafil M 2125 CS;Lauroglycol 90; PEG MW>4000; Plurol Oleique CC 497; poloxamer 124;poloxamer 188; Softigen 701; Softigen 767; Tagat TO; Tween 80;triacetin; triethylcitrate; tributylcitrate; acetyl triethylcitrate;acetyl tributyl citrate; ethyl oleate; ethyl caprylate; ethyl butyrate;triacetin; 2-pyrrolidone; 2-piperidone; N-methylpyrrolidone;N-ethylpyrrolidone; N-hydroxyethyl pyrrolidone; N-octylpyrrolidone;N-laurylpyrrolidone; dimethylacetamide; Miglyol® (Miglyol is aregistered trademark of Cremer Oleo Gmbh & Co. Kg LLP), lanolin,petrolatum, mineral oil and mixtures thereof. The formulations of thepresent invention may comprise a solubilizing agent from about 0.1% toabout 100% of the inactive ingredients or from about 5% to about 85% byweight.

Other components such as preservatives, antioxidants, surfactants,absorption enhancers, viscosity modifiers, bulking agents, diluents,coloring agents, flavoring agents, pH modifiers, sweeteners ortaste-masking agents may also be incorporated into any of thecompositions described as part of the invention. The amount of each ofthese components which may be used will be optimized for eachformulation, in order to obtain a stable product (dosage form) havingthe desired shelf-life. Generally speaking, in embodiments in whichthese components are included, suitable formulations may include fromabout 0.001% to about 20% w/w of a pharmaceutically acceptablepreservative, antioxidant, surfactant, absorption enhancer, viscositymodifier, bulking agent, diluent, coloring agent, flavoring agent, pHmodifier, sweetener or taste-masking agent.

Stabilizer

In certain preferred embodiments, the formulation contains amounts ofone or more pharmaceutically acceptable anti-oxidants in an amounteffective to stabilize the cannabinoid contained therein such that thecannabinoid does not degrade to an unacceptable extent and theformulation is deemed stable for at least eighteen months when placedunder storage conditions selected from refrigerated or room temperature.

In further embodiments of the invention, an effective (stabilizing)amount of one or more pharmaceutically acceptable anti-oxidants is addedto the formulation. The term “anti-oxidant” is used herein to describeany compound or combination of compounds that prevents or slows downcannabinoid oxidation. Any of the known anti-oxidants may be used,including but not limited to anti-oxidants such as butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate,lecithin, Vitamin E tocopherol, sesamin, sesamol, sesamolin, alphatocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid,sodium ascorbate and sodium metabisulphite, as well as chelating agentssuch as disodium EDTA, may also be used to stabilize the cannabinoidformulations of the present invention.

The preparation may also contain anti-oxidant synergists to preventoxidative degradation. Any of the known anti-oxidant synergists may alsobe used in effective amounts, for example disodium edetate.

The amount of anti-oxidant which may be used will be optimized for eachformulation, in order to obtain a stable product (dosage form) havingthe desired shelf-life. Generally speaking, in embodiments in which ananti-oxidant is included, suitable formulations may include from about0.001% to about 20% w/w of a pharmaceutically acceptableanti-oxidant(s). In other preferred embodiments, BHA, or BHT orcombinations thereof, is used as the anti-oxidant in an amount of fromabout 0.001 to about 1%, w/w, and in certain embodiments more preferablyin the range from about 0.01% to about 0.1% w/w. The anti-oxidantpreferably prevents the formation of degradants in the dosage form suchas those mentioned above, namely cannabinol (CBN), cannabidiol (CBD), ordihydrocannabinol to unacceptable levels (e.g., as previously specifiedherein).

Bases

In further embodiments of the invention, effective amounts of one ormore pharmaceutically acceptable organic or inorganic bases are added tothe cannabinoid formulation in order to stabilize the cannabinoid fromundesirable levels of degradation. Examples of suitable organic baseswhich may be effectively used in the cannabinoid formulations of thepresent invention include but are not limited to any pharmaceuticallyacceptable primary, secondary and tertiary organic amines which are GRASingredients (generally regarded as safe), such as methanolamine,ethanolamine, meglumine, other alkylamines (e.g. di-alkyl amines andtri-alkyl amines), and any combination thereof. In embodiments of thepresent invention where organic bases are included, suitableformulations may include from about 0.001% to about 20% w/w of organicbase(s).

In certain preferred embodiments, the amount of organic base(s) in theformulation is from about 0.001% w/w to about 5% w/w, and morepreferably from about 0.005% w/w to about 2% w/w. In other preferredembodiments, the formulations include stabilizing amounts of both one ormore anti-oxidants and one or more base.

In certain other embodiments, the formulations in accordance with thepresent invention are stabilized with an inorganic base e.g, NaOH, orMgOH. Generally, in embodiments in which these components are included,suitable formulations may include from about 0.001% to about 20% w/w ofa pharmaceutically acceptable inorganic base.

Preservatives

Preservatives have bactericidal and fungicidal properties. Parabens arewidely used preservatives in the pharmaceutical industry because oftheir efficacy as preservatives in combination with their long historyof safe use. Parabens work best when they are used in combination sincevarious combinations of parabens allows for the use of lower levelswhile increasing preservative activity. Examples of parabens includemethyl paraben and propyl paraben. In one exemplary embodiment, the oralformulation of the present invention may include 0.001% to 0.1% byweight of methyl paraben and/or 0.001% to 0.1% by weight propyl paraben.

Buffers

In addition the formulations may additionally include physiologicallyacceptable components such as sodium chloride and like materialsconventionally used to achieve isotonicity with typical body fluids.Agents which buffer the pH to maintain a physiologically compatible pHrange to enhance the solubility and stability of the active agentpresent, and the like may also be included in certain embodiments of thepresent invention.

Suitable buffers include, but are not limited to acetate, bicarbonate,citrate, phosphate, pharmaceutically acceptable salts thereof andcombinations or mixtures thereof. When one or more buffers are utilizedin the formulations of the invention, they may be combined, e.g., with apharmaceutically acceptable vehicle and may be present in the finalformulation, e.g., in an amount ranging from about 0.1% to about 20% byweight, more preferably from about 0.5% to about 10% by weight.Therefore, from about 5 mM to about 200 mM concentration of a buffer maybe present in the formulations. The concentration of buffer is such thata pH of the formulation is from about 5 to about 10; preferably fromabout 6 to about 8; more preferably from about 6.5 to about 7.5 and mostpreferably about 7.

In certain other embodiments, the formulations may be isotonic. Isotonicformulations may be provided by the addition of a tonicity agent.Suitable tonicity agents include, but are not limited to anypharmaceutically acceptable sugar, salt or any combinations or mixturesthereof, such as, but not limited to dextrose and sodium chloride. Thetonicity agents may be present in an amount from about 100 mOsm/kg toabout 500 mOsm/kg. In certain preferred embodiments, the tonicity agentis present in an amount from about 200 mOsm/kg to about 400 mOsm/kg andmore preferably from about 280 mOsm/kg to about 320 mOsm/kg.

Sweeteners

In some embodiments, the invention is directed to stable aqueous-basedcannabinoid formulations for oral administration that contain sucrose,fructose, sucralose, sorbitol, xylitol, saccharin, saccharin sodium, orcombinations thereof as a sweetening agent. In certain exemplaryembodiments, the aqueous-based oral dronabinol formulations contain apharmaceutically acceptable sweetener such as sucralose in an amountfrom about 0.01% to about 10% by weight. Other exemplary embodiments mayinclude sweeteners such as xylitol from about 1% to about 25%, saccharinfrom about 0.01% to about 5%, and saccharin sodium from about 0.01% toabout 5% by weight of the formulation.

Viscosity Modifiers

In further embodiments, the invention is directed to formulations thatfurther contain viscosity modifiers including, for example, cellulose orcellulose derivatives such as ethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, carboxymethylcellulose, sodiumhydroxypropylmethylcellulose, methylcellulose, methylethylcellulose,sodium carboxymethylcellulose, Aerosil (silicon dioxide), cetostearylalcohol, cetyl alcohol, stearyl alcohol, Gelucires 33/01, 39/01 and43/01, glyceryl behenate (Compritol 888 A TO), glyceryl palmitostearate(Precirol AT05), Softisans 100, 142, 378 and 649, stearyl alcoholcarbomer, xanthan gum, maltodextrin, acacia, tragacanth, povidone andpolyvinyl alcohol.

Absorption Enhancers

Absorption enhancers for use in accordance with certain embodiments ofthe present invention include, for example, Gelucire 44/14; Gelucire50/13; Tagat TO; Tween 80; isopropyl myristate, polysorbates, sorbitanesters, poloxamer block copolymers, PEG-35 castor oil, PEG-40hydrogenated castor oil, caprylocaproyl macrogol-8 glycerides, PEG-8caprylic/capric glycerides, sodium lauryl sulfate, dioctylsulfosuccinate, polyethylene lauryl ether, ethoxydiglycol, propyleneglycol mono-di-caprylate, glycerol monocaprylate, glyceryl fatty acids(C8-C18) ethoxylated, oleic acid, linoleic acid, glycerylcaprylate/caprate, glyceryl monooleate, glyceryl monolaurate,caprylic/capric triglycerides, ethoxylated nonylphenols, PEG-(8-50)stearates, olive oil PEG-6 esters, triolein PEG-6 esters, lecithin,d-alpha tocopheryl polyethylene glycol 1000 succinate, polycarbonate,sodium glycocholate, sodium taurocholate, cyclodextrins, citric acid,sodium citrate, triacetin, combinations thereof, and the like. Incertain preferred embodiments, the absorption enhancer is triacetin. Incertain preferred embodiments wherein an absorption enhancer is includedin the formulation, the absorption enhancer is included in an amount offrom about 0.001% to about 10% by weight of the formulation, preferablyin an amount of about 0.01% to about 5% by weight of the formulation.

Bulking Agents

Bulking agents may also be used in accordance with certain embodimentsof the present invention including for example, microcrystallinecellulose, mannitol, xylitol, starches and the like. In certainpreferred embodiments, the bulking agent is mannitol. In certainpreferred embodiments wherein bulking agent is included in theformulation, the bulking agent is included in an amount of from about0.001% to about 10% by weight of the formulation, preferably in anamount of about 0.01% to about 5% by weight of the formulation.

Gelling Agents

The formulations of the present invention also may contain suitablegelling or suspension agents include carbomers such as Carbopol®(Carbopol is a registered trademark of Lubrizol Advanced Materials,Inc.), modified cellulose derivatives, naturally-occurring, synthetic orsemi-synthetic gums such as xanthan gum, acacia and tragacanth, modifiedstarches, co-polymers such as those formed between maleic anhydride andmethyl vinyl ether, colloidal silica and methacrylate derivatives soldunder the trade name Eudragit™, or a mixture thereof.

In further embodiments, additional excipients compatible with theformulations of the invention may be incorporated into the liquid drugformulation, if needed, such as known surfactants (e.g. Capryol 90;Cremophor RH40; Gelucire 44/14; Gelucire 50/13; Imwitor 91; Imwitor 308;Imwitor 380; Imwitor 742; Imwitor 780K; Imwitor 928; Imwitor 988;Labrafil M 1944 CS; Labrafil M 2125 CS; Lauroglycol 90; Tagat TO; Tween80; and mixtures thereof); and emulsifiers (e.g., Gelucire 44/14;Gelucire 50/13; Imwitor 91; Imwitor 308; Imwitor 380; Imwitor 742;Imwitor 780K; Imwitor 928; Imwitor 988; poloxamer 124; poloxamer 188;Tagat TO; Tween 80; lecithin; lysolecithin; phosphatidylcholine;phosphatidylethanolamine; phosphatidylglycerol; phosphatidic acid;phosphatidylserine; lysophosphatidylcholine;lysophosphatidylethanolamine; lysophosphatidylglycerol; lysophosphatidicacid; lysophosphatidylserine; PEG-phosphatidylethanolamine;PVP-phosphatidylethanolamine; sodium lauryl sulfate and mixturesthereof).

Other additives conventionally used in pharmaceutical compositions canbe included, and these additives are well known in the art. Suchadditives include pharmaceutically acceptable detackifiers, anti-foamingagents, chelating agents, viscomodulators, tonicifiers, flavorants,colorants odorants, opacifiers, suspending agents, binders, fillers,plasticizers, lubricants, and mixtures thereof. The amounts of suchadditives can be readily determined by one skilled in the art, accordingto the particular properties desired, keeping in mind the possibilitythat any such additives should preferably not negatively impact thestability of the final formulation.

Suitable coloring agents include red, black and yellow iron oxides andFD&C dyes such as FD&C Blue No. 2, FD&C Red No. 40, and the like.Suitable flavoring agents include mint, raspberry, licorice, orange,lemon, grapefruit, caramel, vanilla, cherry grape flavors, combinationsthereof, and the like. Suitable sweeteners include sucralose, xylitol,saccharin, and the like. Suitable pH modifiers include citric acid,tartaric acid, phosphoric acid, hydrochloric acid, maleic acid, sodiumhydroxide, and the like. Suitable sweeteners include aspartame,acesulfame K, thaumatic, and the like. Suitable taste-masking agentsinclude sodium bicarbonate, ion-exchange resins, cyclodextrin inclusioncompounds, adsorbates, and the like.

It is recognized that pharmaceutical excipients may perform more thanone function, and are therefore characterized as having different usesdepending on the particular application. While the use of an excipientin the context of a particular formulation may determine the function ofthe excipient, the inclusion of any particular excipient into any one ormore category as set forth above is not meant to limit the function ofthat excipient.

Although the ingredients of the formulations of the present inventionare characterized herein as percentage based on weight, one skilled inthe art will appreciate that scaled-up versions of the formulationsspecifically described herein may be characterized instead on a volumepercentage basis. Where the density of a particular component is 1 g/mlthe amount of the component based on volume and weight will be the same.Where the density deviates from 1 g/ml, the amounts based on weight orvolume will differ accordingly.

Additional Drugs

Cannabinoids such as dronabinol may be used alone or in combination withother cannabinoids or Cannabis-derived molecules (synthetic or natural)or other medications. Those skilled in the art will readily recognizethat, for example, in the case of AIDS wasting syndrome, the patientwill likely also be taking drugs that combat the AIDS virus. Similarly,those skilled in the art will readily recognize that patients receivingchemotherapy for cancer may also receive other antiemetics, and cancerpatients seeking to relieve pain are likely to receive opioids as wellas nonsteroidal anti-inflammatory agents. The formulations and methodsof the invention may further include one or more additionaltherapeutically active agents, such as, for example, non-narcoticanalgesics such as acetaminophen or aspirin, opioid or opiateanalgesics, non-steroidal anti-inflammatory drugs (NSAIDs, for example,non-selective cyclooxygenase inhibitors and COX-2 inhibitors),anti-emetics (for example, 5-hydroxytryptamine₃ (5-HT₃) inhibitors suchas ondansetron, granisetron, tropisetron, palonosetron, dolasetron, andmirtazapine) and steroids (for example megestrol acetate, oxandrolone,oxymetholone, and dexamethasone). In certain embodiments of theinvention, a second therapeutically active drug including but notlimited to the above-mentioned drugs, is incorporated into the oralcannabinoid dosage form. In yet other embodiments, the secondtherapeutically active drug is separately administered to the patient inconjunction with the oral cannabinoid dosage form. The sequence in whichthe therapeutic agents are administered is not narrowly critical.“Combination therapy” embraces the administration of the therapeuticagents as described above in further combination with other biologicallyactive ingredients, such as, but not limited to, a pain reliever, suchas a steroidal or nonsteroidal anti-inflammatory drug, or an agent forimproving stomach motility, for example, and with non-drug therapies,such as, but not limited to, surgery.

The therapeutic compounds that make up the combination therapy may alsobe administered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thus, aregimen may call for sequential administration of the therapeuticcompounds with spaced-apart administration of the separate, activeagents. The time period between the multiple administration steps mayrange from, for example, a few minutes to several hours to days,depending upon the properties of each therapeutic compound such aspotency, solubility, bioavailability, plasma half-life and kineticprofile of the therapeutic compound, as well as depending upon theeffect of food ingestion and the age and condition of the subject.Circadian variation of the target molecule concentration may alsodetermine the optimal dose interval.

The therapeutic compounds of the combined therapy whether administeredsimultaneously, substantially simultaneously, or sequentially, mayinvolve a regimen calling for administration of one therapeutic compoundby oral route and another therapeutic compound by an oral route, apercutaneous route, an intravenous route, an intramuscular route, or bydirect absorption through mucous membrane tissues. Whether thetherapeutic compounds of the combined therapy are administered orally,rectally, topically, buccally, sublingually, or parenterally (forexample, subcutaneous, intramuscular, intravenous and intradermalinjections, or infusion techniques), separately or together, each suchtherapeutic compound will be contained in a suitable pharmaceuticalformulation of pharmaceutically-acceptable excipients, diluents or otherformulations components.

Advantages of the Invention

The branded product Marinol® (Dronabinol solution in soft gelatincapsules; Marinol is a registered trademark of Unimed Pharmaceuticals,LLC and is available form AbbVie Inc.) is highly unstable at roomtemperature. Therefore the manufacturer of Marinol® (UnimedPharmaceuticals Inc.) recommends that the product be stored atrefrigerated (2-8.degree. C.) or cool (8-15.degree. C.) conditions(Marinol® package label, Physicians' Desk Reference®, Ed. 2003). Also,aqueous-based cannabinoid formulations in the prior art are notconsidered stable when the aqueous-based component of the carrierexceeds about 20% w/w. At higher concentrations of water, thecannabinoid readily precipitates. Unlike the prior art cannabinoidformulations, the present invention provides a aqueous-based cannabinoid(e.g., dronabinol) formulation drug product that is preferably stable atall conditions—refrigerated, cool and room temperature. In addition, theprovided formulations have in vivo absorption variability of less than50%. Factors contributing to the improved stability, particularly atroom temperature, of the present invention include the use of specificsolvents/diluents and co-solvents in conjunction with the addition ofeffective stabilizing amounts of preservatives and antioxidants.

In addition, in certain exemplary embodiments, the cannabinoidformulations of the present invention improve the delivery of thecannabinoid with respect to the extent, rate, and/or consistency of invivo absorption from the location of administration.

Uses of the Present Invention

The formulations of the present invention are useful in treatment andprevention of a very wide range of disorders, including, for example,nausea, vomiting, anorexia, cachexia, pain, gastrointestinal tractdistress (such as heartburn, indigestion, stomachache, sour stomach),inflammatory bowel disease, Crohn's disease, gastritis, irritable bowelsyndrome, ulcerative colitis, migraine headaches, postmenstrualsyndrome, Alzheimer's dementia, agitation, muscle spasms and otherinvoluntary movement disorders, Parkinson's disease andParkinsonian-type symptoms, spasticity as result of multiple sclerosis,glaucoma and anxiety disorders. Cannabinoids such as dronabinol havealso been reported as showing other biological activities which lendthemselves to possible therapeutic applications, such as in thetreatment of migraine headaches, spinal cord injury, anxiety, glaucomaand as an analgesic (e.g., to treat neuropathic pain). Cannabinoids suchas dronabinol may be used together with opioid analgesics in asynergistic way to relieve pain; advantages of the combination mayinclude decreased administration of opioids (leading to decreased sideeffects) and may be opioid-sparing (i.e., allowing for a reduced dose ofopioid to achieve an equivalent effect). Dronabinol has also been usedin the treatment of cancer cachexia (where the loss of appetite inducesmalnutrition in cancer patients). It has also been used to treatmovement disorders including dystonia, Huntington's disease, Parkinson'sdisease and Tourette's syndrome; epilepsy, and for appetite stimulationin Alzheimer's disease. The use of cannabinoid formulations prepared inaccordance with the present invention is contemplated for any and all ofthe above uses, and any other use known or which become known to thoseskilled in the art.

Routes of Administration

The formulations of the present invention are preferably administeredorally, e.g. via oral solution or sublingually. However, one skilled inthe art will appreciate that the stabilized aqueous-based cannabinoidformulations of the present invention are not limited to administrationby these routes, and can be administered via the nasogastric route, anintramuscular route, or by direct absorption through mucous membranetissues, pulmonary, intravenous; transdermal, and ophthalmicadministration as well as vaginal, rectal, parenteral or transmucosal(e.g., buccal or sublingual) administration. Thus, the dosage form canbe converted from a solution to a suspension, emulsion, suppository,spray, aerosol, gel, drops, syrup, elixir, or other dosage form, asdesired.

Oral Solution Formulations

The present invention is formulated into a stable aqueous-basedcannabinoid formulation by first preparing a stable aqueous-basedformulation in accordance with the present invention, and then furtheradding a sweetening agent, taste-masking agent, flavoring agent,coloring agent, viscosity modifying agent or combinations thereof.

In accordance with oral solution formulations of the current inventionwhere the cannabinoid is dronabinol, the dronabinol concentration isfrom about 0.05 mg/ml to about 20 mg/ml; preferably from about 0.5 mg/mlto about 10 mg/ml; and more preferably about 5 mg/ml (or about 0.541%w/w). The dose of dronabinol provided by the oral solution formulationsis preferably from about 2.5 mg to about 20 mg dronabinol.

In certain embodiments, the present invention further contains aviscosity modifying agent, e.g. hydroxypropylcellulose orpolyvinylpyrrolidone (povidone or PVP).

In certain embodiments the invention is directed to stable aqueous-basedcannabinoid formulations for oral administration that contains sucrose,fructose, sorbitol, xylitol, saccharin, saccharin sodium or combinationsthereof as a sweetening agent.

One of skill will readily appreciate that the stable aqueous-basedcannabinoid oral liquid formulations of the present invention can beincorporated into any pharmaceutically acceptable single-dose ormulti-dose container made from any pharmaceutically acceptable material,(e.g., glass or plastic) to allow for oral dosing of the formulation.

Nebulizer Formulations

Pulmonary administration offers a route of delivery that is suitable foradministration of drugs wherein the drug properties make it difficultfor oral administration, or where the physical state of the specificpatient does not make oral administration desirable (e.g., vomiting,compromised gastrointestinal tract).

In certain embodiments, the formulations of the present invention aredesigned for pulmonary delivery via a nebulizer. Nebulizers are broadlyknown to those of skill in the art and the invention is not limited toany specific type of nebulizer.

In certain embodiments, formulations suitable for intrapulmonaryadministration are administered into the lung as aerosolized particleshaving a mean mass median aerodynamic diameter in the range of fromabout 0.01 to about 15 microns. Preferably the created particles have amean mass median aerodynamic diameter in the range of from about 1 toabout 10 microns, more preferably from about 1 to about 5 microns.

Sublingual Formulations

The oral cavity offers a simple, painless method of cannabinoidadministration. Within the oral cavity, there are three generallyrecognized routes of administration of an active agent, namely local,buccal and sublingual.

Local delivery is mainly limited to applications regarding disruptionsoccurring within the oral cavity itself, such as a canker sore.

The buccal mucosa area encompasses the mucosal membranes of the innerlining of the cheeks. The buccal mucosa is however, less permeable thanthe sublingual area. One of the major disadvantages associated withbuccal mucosa delivery of an active agent has been the relatively lowpassage of active agents across the mucosal epithelium, therebyresulting in low agent bioavailability, which translates into asubstantial loss of usable active agent within each dosage.

Sublingual delivery is achieved through the mucosal membranes lining thefloor of the mouth. Because of the high permeability and the rich bloodsupply, transport via the sublingual route results in rapid in vivoabsorption. Sublingual delivery is also beneficial in providing adelivery route appropriate for highly permeable drugs with shortdelivery period requirements and an infrequent dosing regimen.

The sublingual formulations of the present invention are usefulmanagement of anorexia associated with weight loss in patients with AIDSand nausea and vomiting associated with cancer chemotherapy.

Sublingual administration of dronabinol, a pharmaceutically acceptablesalt thereof, or derivative thereof, in accordance with the presentinvention may be particularly beneficial in the patient with cancer whois unable to tolerate oral administration because of nausea andvomiting, dysphagia as a result of disease, or parenteral administrationbecause of decreased venous access, emaciation, or coagulation defects.Sublingual administration of dronabinol in accordance with the presentinvention preferably has potential advantages of even greater ease ofuse and rapid onset of appetite stimulant or antiemetic action.Furthermore, because sublingual venous drainage is systemic rather thanportal, hepatic first-pass elimination may be avoided. The presentinvention preferably provides therapeutic formulations and methods forsolutions of dronabinol, a pharmaceutically acceptable salt thereof, orderivative thereof to be delivered by sublingual spray pumps.

In certain preferred embodiments, the sublingual administration ofdronabinol, a pharmaceutically acceptable salt thereof, or derivativethereof, is advantageous over other forms of administration in that itdoes not require injection using a syringe and needle, and avoids theneed for formulating unit dose oral formulations. Preferably thesublingual administration of dronabinol, a pharmaceutically acceptablesalt thereof, or derivative thereof, in accordance with the presentinvention is suitable for self-administration.

In certain embodiments, the formulations of the present invention areadvantageous in that propellants such as hydrofluorocarbon propellantssuch as volatile chlorofluocarbons (e.g. propellant 12), volatilehydrofluoroalkanes (e.g. 1,1,1,2-tetrafluoroethane and1,1,1,2,3,3,3-heptafluoro-n-propane) and volatile alkanes (e.g. propane,butane) are not required to deliver the dronabinol, a pharmaceuticallyacceptable salt thereof, or derivative thereof, sublingually to thepatient.

Preferably the formulations of the present invention are delivered asliquid droplets having a mean diameter of at least about 10 microns,preferably at least about 20 microns, more preferably a mean diameter offrom about 20 to about 200 microns. Most preferably the formulations aredelivered as liquid droplets have a size distribution of from about 5microns to about 500 microns, preferably from about 10 microns to about200 microns, preferably from about 20 microns to about 100 microns, morepreferably from about 30 microns to about 70 microns.

Preferably the delivery of the formulation of the present invention tothe sublingual mucosa via spray results in a rapid in vivo absorption ofthe dronabinol, a pharmaceutically acceptable salt thereof, orderivative thereof.

In certain embodiments, the formulations of the present invention aredesigned for sublingual administration.

Intravenous Formulations

Intravenous administration also provides a route of administration whereother routes such as oral, pulmonary and sublingual are not desired orsuitable. The intravenous route of administration is particularlyadvantageous where irregular in vivo absorption is a concern. Theseformulations are prepared in accordance with the procedure used toprepare the above-mentioned solutions. In certain embodiments, theformulations may also contain pH modifiers and or tonicity modifyingagents to limit the irritation to the blood vessel upon administration.The formulations are then introduced into an IV infusion bag prior toadministration to a patient, either directly or mixed with water priorto being mixed with the solution in the IV infusion bag. The dosageranges will vary with the choice of cannabinoid. In certain embodiments,the dose will be adjusted to provide a dose that is therapeuticallyequivalent to the oral dose of Marinol®. One of skill will appreciatethat the dose will typically be lower than the dose delivered throughother routes of administration as the intravenous route providesessentially complete bioavailability of the administered dose.

In certain embodiments where the formulation contains dronabinol, theintravenous dose is from about 0.01 mg to about 50 mg.

Ophthalmic Preparations

Ophthalmic administration provides a route of administration where theintended action involves the ocular system. Ophthalmic formulations areprepared in accordance with the procedure described for preparing theabove-mentioned formulations. In certain embodiments, the ophthalmicpreparations will also contain pH modifiers and or tonicity modifyingagents in order to substantially prevention the irritation to the eyeupon administration.

In certain other embodiments, the ophthalmic formulations are ointments.In certain other embodiments, the formulations contain lanolin,petrolatum, a high molecular weight glycol, e.g., PEG-400, mineral oil,or combinations thereof. In certain embodiments, the formulationsfurther comprise water.

The ophthalmic formulation may then be transferred into single ormulti-dose containers, made from pharmaceutically acceptable materialssuitable for ophthalmic administration. The dosage ranges will vary withthe choice of cannabinoid. The cannabinoid will be present in aconcentration such that a dose will provide a therapeutically effectiveamount of cannabinoid to treat a condition of the eye, e.g., glaucoma.

In certain embodiments of the invention, the ophthalmic formulationcontains dronabinol in a concentration of about 1% by weight. In certainother embodiments, the dosage provides from about 0.01 mg to about 10 mgdronabinol, preferably from about 0.5 mg to about 5 mg, and morepreferably from about 1 mg to about 3 mg.

The following examples illustrate various aspects of the presentinvention, and are set forth to assist in understanding the invention.These examples should not be construed as specifically limiting theinvention described and claimed herein. Variations of the invention,including the substitution of all equivalents now known or laterdeveloped, which would be within the purview of those skilled in theart, and changes in formulation or minor changes in experimental design,are considered to fall within the scope of the invention and appendedclaims.

EXAMPLES Example 1 Dronabinol Oral Solution 5 mg Dose Versus 5 mgDronabinol Capsules Manufacturing Procedure for Aqueous-Based OralCannabinoid Solution

The investigational test compound Delta-9-tetrahydrocannabinol(Delta-9-THC) was obtained. All other chemicals used in the formulationswere of a pharmaceutical grade. Delta-9-THC (dronabinol) is chemicallysynthesized as per procedures known to those skilled in the art and issupplied as a clear, amber colored resinous solid at room temperature.

First, a vacuum is applied to the dronabinol before heating. Thedronabinol is then liquefied by heating in an oven at 90 degrees C.under vacuum for about sixty (60) to one hundred eighty (180) minutesNext, the liquefied or molten dronabinol is quickly transferred to aseparate stock of dehydrated alcohol and the contents are mixed at 50degrees C.+/−5 degrees C. while being sparged with nitrogen in anairtight container until the dronabinol is completely dissolved in thedehydrated alcohol to create a dronabinol bulk solution that is 6%dronabinol by weight (6% w/w).

An excipient solution is created by dissolving butylated hydroxylanisole (BHA), sucralose, methyl paraben, and propyl paraben indehydrated alcohol and sucralose in dehydrated alcohol in an air tighttank/container sparged with nitrogen for about fifteen (15) to thirty(30) minutes. Amounts of PEG 400, propylene glycol, and water are thenadded while continuing to mix in the air tight tank/container spargedwith nitrogen. Next, a calculated amount of dronabinol bulk solution isadded to the excipient solution and mixed for about fifteen (15) minuteswhile continuing to be sparged with nitrogen in an airtight container.An amount of dehydrated alcohol is then added and mixed for about ten(10) minutes while the mixture continues to be sparged with nitrogen inan airtight container to give a final aqueous-based oral dronabinolsolution having 0.541% weight dronabinol. The final aqueous-based oraldronabinol solution is then filtered and filled into 30 ml amber glassbottles. Finally, the bottles are manually labeled and placed intolabeled cartons.

One exemplary formulation of the cannabinoid solution of the presentinvention is as follows:

TABLE 1 Aqueous-based Cannabinoid Solution (A) Quality % w/w ComponentStandard Function (Theoretical) Dronabinol USP Active 0.541 Ingredient(5 mg/mL) Butylated Hydroxy USP Antioxidant 0.01 Anisole (BHA) SucraloseNF Sweetener 0.05 Methyl Paraben USP Preservative 0.02 Propyl ParabenUSP Preservative 0.02 PEG 400 USP Co-solvent 12.0 Propylene Glycol USPCo-solvent 5.5 Water USP Solvent/Diluent 31.9 Dehydrated Alcohol USPCo-solvent QS* TOTAL 100 *Dehydrated Alcohol content is 50.0% w/w

Pharmacokinetic and Bioavailability Analysis

Protocol was an open-label, 2-treatment, 4-period, 2-sequence,replicate, single-dose, randomized crossover study of the comparativebioavailability of the aqueous-based oral dronabinol solution of thepresent invention and Marinol® 5 mg Capsules (Unimed Pharmaceuticals).Eighty-eight (88) healthy male and female volunteers were randomlyassigned to 1 of 2 treatment sequences, Sequence 1 (T→R→T→R) or Sequence2 (R→T→R→T), where T=the test product, Dronabinol Solution, and R=thereference product, Marinol® capsules.

Eighty-eight (88) subjects were enrolled into the study. Three (3)completed only the first period and no samples were analyzed. One (1)subject completed the first 2 periods, 2 subjects completed 3 of the 4periods and samples from those periods were analyzed. The analysispopulation was therefore comprised of 85 subjects, 82 of whom completedall 4 treatments, 2 that completed 3 of the 4 treatments, and 1 thatcompleted 2 of the 4 treatments.

Aqueous-Based Oral Cannabinoid Solution 5 mg/ml

Safety was assessed using the following parameters: physicalexaminations, vital signs, clinical laboratory evaluations, ECGs,concomitant medication assessments, and adverse event assessments. Inaddition, subjects were observed for a psychotic episode (e.g.hallucinations, paranoid delusions, personality changes, disorganizedthinking) and monitored until their mental status returned to normalwhile confined to the study site.

Statistical Methods

Data from 85 subjects who completed the study were included in thepharmacokinetic and statistical analyses.

The following pharmacokinetic parameters were calculated: peakconcentration in plasma (C_(max)), time to peak concentration (T_(max)),elimination rate constant (λ_(z)), terminal half-life (T_(1/2)), areaunder the concentration-time curve from time-zero to the time of thelast quantifiable concentration (AUC_(last)), and area under the plasmaconcentration time curve from time-zero extrapolated to infinity(AUC_(inf)).

Results and Conclusions

Results of the pharmacokinetic and statistical analyses for theAqueous-based Oral Cannabinoid Solution (A) of the present invention andthe Marinol® reference product is shown in Table 2. Table 2 shows thepharmacokinetic parameters of dronabinol comparing the Aqueous-basedOral Cannabinoid Solution (Test A) of the present invention and theMarinol® reference product.

TABLE 2 Summary of PK parameters for dronabinol with replicates combinedafter oral administration of single 5 mg doses of Dronabinol Solutionand Marinol ® capsule to healthy volunteers under fasted conditions.Test Formulation (A) Marinol ® Parameter* (Test) (Reference) Cmax(ng/Ml)  2.4 ± 1.30 (168) 2.17 ± 1.22 (168) Tmax (h) 1.00 (168) 1.00(168) [0.25-4.00] [0.50-6.00] AUC(0-6) (hxng/Ml) 3.55 ± 1.63 (168) 3.19± 1.78 (165) AUC(0-12) (hxng/Ml)† 4.12 ± 1.75 (158) 4.85 ± 2.08 (74) AUC(0-t) (hxng/Ml) 4.23 ± 1.97 (168) 3.56 ± 2.18 (168) AUC(inf)(hxng/Ml) 4.48 ± 1.94 (150) 3.48 ± 2.18 (143) λz (h⁻¹) 0.1253 ± 0.0624(150) 0.3349 ± 0.1526 (143) t½ (h) 7.51 ± 5.70 (150) 3.34 ± 4.46 (143)*Arithmetic mean ± standard deviation (N) except Tmax for which themedian (N) [Range] is reported.

The time to peak mean dronabinol concentration for the Aqueous-basedOral Cannabinoid Solution of the present invention is shorter than thetime to peak mean dronabinol concentration for the Marinol® referenceproduct. The time to peak mean dronabinol concentration for theAqueous-based Oral Cannabinoid Solution ranged from about 0.25 hoursafter administration to about 4.00 hours after administration while thetime to peak mean dronabinol concentration for the Marinol® referenceproduct ranged from about 0.50 hours after administration to about 6.00hours after administration. With respect to THC levels, pharmacokineticparameters such as T_(max), C_(max), and AUC show less variability afterAqueous-based Oral Cannabinoid Solution administration compared to theMarinol® reference product. The systemic in vivo absorption of THC ismore consistent with the Aqueous-based Oral Cannabinoid Solution of thepresent invention than it is with the Marinol® reference product. Thepeak mean dronabinol concentration for the Aqueous-based OralCannabinoid Solution of the present invention ranged from about 1.12ng/ml to about 3.72 ng/ml while the peak mean dronabinol concentrationfor the Marinol® reference product ranged from about 0.095 ng/ml toabout 3.39 ng/ml.

Stability Data

Table 3 includes stability data for the Aqueous-based Oral DronabinolSolution of the present invention. The Aqueous-based Oral DronabinolSolution of the present invention was stored at 5 degrees C., 25 degreesC., and 40 degrees C. and potency and impurities were measured monthlyfor three months and then at 6 months, 9 months, and 12 months. Percentpotency and total impurities were determined by HPLC/UV analysis. As canbe seen from the results, the Aqueous-based Oral Dronabinol Solution ofthe present invention maintained its potency within 3% at alltemperatures and total impurities were less than 5%.

TABLE 3 Clinical Aqueous-based Oral Solution 0 Time 1 Month 2 Month %Total % Total % Total Temperature (° C.) % Potency Impurities % PotencyImpurities % Potency Impurities 5 100.70 1.23 25 100.70 1.23 40 100.701.23 100.20 1.91 99.50 2.46 Clinical Aqueous-based Oral Solution 3 Month6 Month % Total % Total Temperature (° C.) % Potency Impurities %Potency Impurities 5 102.20 1.25 101.30 1.51 25 100.90 1.57 100.40 2.0640 99.30 2.72 97.5 4.49 Clinical Aqueous-based Oral Solution 9 Month 12Month % Total % Total Temperature (° C.) % Potency Impurities % PotencyImpurities 5 101.10 1.44 100.50 1.65 25 100.70 2.33 98.80 2.78

Example 2 Other Exemplary Formulations and Stability Data

Table 4 contains five additional exemplary formulations of theAqueous-based Oral Dronabinol Solution of the present invention whileTables 5-14 show stability data relating to the respective formulationsthat demonstrate different combinations of aqueous and organiccomponents that can be used to achieve stable Dronabinol solution.

TABLE 4 Oral Solution % w/w COMPONENT HG026014 HG026015 HG026016HG026017 HG0260719 Dronabinol 0.5 0.5 0.5 0.5 0.5 BHA 0.01 0.01 0.01EDTA 0.1 0.1 Sucralose 0.3 0.05 Cherry flavor 0.05 Methyl paraben 0.02Propyl paraben 0.02 Glycerine 50 Alcohol (deh) 50 50 50 37 49.95 PEG 40012 12 12 12 Propylene glycol 5.5 5.5 5.5 5.5 Phosphate buffer, pH 731.99 31.69 31.9 12.4 Water 31.9

TABLE 5 Stability Data HG026014 0 Week 1 Week 2 Week % Total % Total %Total Temperature (° C.) % Potency Impurities % Potency Impurities %Potency Impurities 25 99.54 2.21 40 99.54 2.21 97.91 2.16 97.80 2.11 5599.54 2.21 98.19 2.28 98.41 2.43 HG026014 3 Week 4 Week 6 Week % Total %Total % Total Temperature (° C.) % Potency Impurities % PotencyImpurities % Potency Impurities 25 99.23 2.04 40 98.18 2.40 100.48 2.5755 98.45 3.19 101.37 3.38

TABLE 6 Stability Data HG026015 0 Week 1 Week 2 Week % Total % Total %Total Temperature (° C.) % Potency Impurities % Potency Impurities %Potency Impurities 25 99.93 2.20 40 99.93 2.20 98.07 2.42 97.50 2.26 5599.93 2.20 97.28 2.06 97.97 2.46 HG026015 3 Week 4 Week 6 Week % Total %Total % Total Temperature (° C.) % Potency Impurities % PotencyImpurities % Potency Impurities 25 98.47 2.46 40 98.52 2.29 99.41 2.4955 96.28 3.30 99.06 3.70

TABLE 7 Stability Data HG026016 0 Week 1 Week 2 Week % Total % Total %Total Temperature (° C.) % Potency Impurities % Potency Impurities %Potency Impurities 25 99.14 2.11 40 99.14 2.11 101.20 2.42 98.81 2.22 5599.14 2.11 97.66 2.26 97.46 2.74 HG026016 3 Week 4 Week 6 Week % Total %Total % Total Temperature (° C.) % Potency Impurities % PotencyImpurities % Potency Impurities 25 99.47 1.94 40 98.84 2.20 99.53 2.5855 97.68 3.18 100.25 3.61

TABLE 8 Stability Data HG026017 0 Week 1 Week 2 Week % Total % Total %Total Temperature (° C.) % Potency Impurities % Potency Impurities %Potency Impurities 25 100.06 2.00 40 100.06 2.00 100.34 2.14 97.89 2.3455 100.06 2.00 96.67 2.83 94.27 3.21 HG026017 3 Week 4 Week 6 Week %Total % Total % Total Temperature (° C.) % Potency Impurities % PotencyImpurities % Potency Impurities 25 99.70 2.17 40 100.95 2.88 101.55 3.0755 96.53 4.39 97.02 5.19

TABLE 9 Stability Data HG026079 0 Week 1 Week 2 Week % Total % Total %Total Temperature (° C.) % Potency Impurities % Potency Impurities %Potency Impurities 25 108.12 1.22 40 108.12 1.22 103.72 2.25 55 108.121.22 105.38 2.11 102.46 3.11 HG026079 3 Week 4 Week 6 Week % Total %Total % Total Temperature (° C.) % Potency Impurities % PotencyImpurities % Potency Impurities 25 100.02 1.54 40 100.55 2.14 55 93.103.65 98.12 4.89

Table 10 contains five additional exemplary formulations of theAqueous-based Oral Dronabinol Solution of the present invention whileTables 11-14 show stability data relating to the respectiveformulations.

TABLE 10 Formulations % w/w Component AK035144 AK035145 AK035146AK035147 Dronabinol 0.541 0.541 0.541 0.541 BHA 0.01 0.01 0.01 — BHT — —0.01 — Sucralose 0.05 0.05 0.05 0.05 Methyl Paraben — — — — PropylParaben — — — — Dehydrated 50 50 50 50 Alcohol PEG 400 12 — 12 12Propylene glycol 37.399 49.399 37.389 37.409 Water — — — — TOTAL 100 100100 100

TABLE 11 Stability Data AK035144 0 Week 1 Week 2 Week % Total % Total %Total Temperature (° C.) % Potency Impurities % Potency Impurities %Potency Impurities 40 113.12 1.40 108.38 2.51 107.50 2.05 55 113.12 1.40108.38 2.51 107.09 3.21 AK035144 3 Week 4 Week % Total % % TotalTemperature (° C.) % Potency Impurities Potency Impurities 40 105.462.47 55 106.77 4.08

TABLE 12 Stability Data AK035145 0 Week 1 Week 2 Week % Total % Total %Total Temperature (° C.) % Potency Impurities % Potency Impurities %Potency Impurities 40 111.24 1.47 104.89 1.57 55 111.24 1.47 105.27 1.63106.82 2.00 AK035145 3 Week 4 Week % Total % Total Temperature (° C.) %Potency Impurities % Potency Impurities 40 104.18 1.75 55 107.46 2.38

TABLE 13 Stability Data AK035146 0 Week 1 Week 2 Week % Total % Total %Total Temperature (° C.) % Potency Impurities % Potency Impurities %Potency Impurities 40 110.19 1.47 104.61 1.86 55 110.19 1.47 104.67 2.09104.39 2.13 AK035146 3Week 4 Week % Total % Total Temperature (° C.) %Potency Impurities % Potency Impurities 40 102.73 2.06 55 105.41 3.33

TABLE 14 Stability Data AK035147 0 Week 1 Week 2 Week % Total % Total %Total Temperature (° C.) % Potency Impurities % Potency Impurities %Potency Impurities 40 114.03 1.42 106.38 3.21 55 114.03 1.42 104.64 5.33101.35 8.43

It will be understood by those skilled in the art that variations of thecomponent weight percentages of the dronabinol solutions describedherein may occur while still achieving the results of a better in vivoabsorption profile with faster onset and lower inter-subjectavailability than prior art soft gelatin capsules containing dronabinol,and enhanced stability and equal or improved safety profiles over priorart soft gelatin capsules containing dronabinol.

Weight percentage ranges of some components for the Dronabinol Solutiondescribed may include:

-   -   Alcohol: 15-65% w/w    -   Propylene glycol: 0-50% w/w    -   Polyethyleneglycol (PEG): 0-50% w/w    -   Water: 0-40% w/w    -   Sweetener (e.g., Sucralose): 0-10% w/w, and preferably 0-2% w/w    -   Anti-oxidants (e.g., BHA, BHT, ascorbyl palmitate, EDTA,        lecithin, Vitamin E TPGS, tocopherol etc.): 0-10% w/w, and        preferably, 0-2% w/w    -   Preservatives (parabens): 0-5% w/w and preferably, 0-1% w/w    -   Flavoring agent: 0-5% w/w and preferably, 0-1% w/w

Other agents (e.g., viscosifiers, solubilizers such as surfactants,colorants) can also be included.

Many other variations of the present invention will be apparent to thoseskilled in the art and are meant to be within the scope of the claimsappended hereto. The foregoing specification alludes to beliefs,hypothesis and conclusions of the inventors based on his experience inthe field, the reports of others (such as those identified in thepublications identified herein), and experiments conducted and reportedherein, and are provided for purposes of (possible) explanation only andare not meant to limit the invention in any manner whatsoever.

Example 3 Dronabinol Oral Solution 4.25 mg Dose Versus 5 mg DronabinolCapsules

The dronabinol solution of example 1 was used in another bioavailabilitystudy. However, in this study, 0.85 mL of the solution was administeredto subjects equating to a 4.25 mg dose.

Pharmacokinetic and Bioavailability Analysis

Protocol was an open-label, 2-treatment, 4-period, 2-sequence,replicate, single-dose, randomized crossover study of the comparativebioavailability of the aqueous-based oral dronabinol solution of thepresent invention and Marinol® 5 mg Capsules (Unimed Pharmaceuticals).Fifty-two (52) healthy male and female volunteers were randomly assignedto 1 of 2 treatment sequences, Sequence 1 (T→R→T→R) or Sequence 2(R→T→R→T), where T=the test product, Dronabinol Solution, and R=thereference product, Marinol® capsules.

Fifty-two (52) subjects were enrolled into the study. One (1) subjectcompleted only the first period and no samples were analyzed. One (1)subject completed only the first 2 periods. The analysis population wastherefore comprised of 52 subjects, 50 of whom completed all 4treatments, 1 that completed 1 of the 4 treatments and 1 that completed2 of the 4 treatments.

Aqueous-Based Oral Cannabinoid Solution 5 mg/ml

Safety was assessed using the following parameters: physicalexaminations, vital signs, clinical laboratory evaluations, ECGs,concomitant medication assessments, and adverse event assessments. Inaddition, subjects were observed for a psychotic episode (e.g.hallucinations, paranoid delusions, personality changes, disorganizedthinking) and monitored until their mental status returned to normalwhile confined to the study site.

Statistical Methods

Data from 50 subjects who completed the study were included in thepharmacokinetic and statistical analyses.

The following pharmacokinetic parameters were calculated: peakconcentration in plasma (C_(max)), time to peak concentration (T_(max)),elimination rate constant (λ_(z)), terminal half-life (T_(1/2)), areaunder the concentration-time curve from time-zero to the time of thelast quantifiable concentration (AUC_(last)), and area under the plasmaconcentration time curve from time-zero extrapolated to infinity(AUC_(inf)).

Results and Conclusions

Results of the pharmacokinetic and statistical analyses for theAqueous-based Oral Cannabinoid Solution (A) of the present invention andthe Marinol® reference product is shown in Table 15. Table 15 shows thepharmacokinetic parameters of dronabinol comparing the Aqueous-basedOral Cannabinoid Solution (Test A) of the present invention and theMarinol® reference product.

TABLE 15 Summary of PK parameters for dronabinol with replicatescombined after oral administration of single 4.25 mg doses of DronabinolSolution and 5 mg dose of Marinol ® capsule to healthy volunteers underfasted conditions. Test Formulation (A) Marinol ® Parameter* (Test)(Reference) Cmax (ng/mL)   1.95 ± 1.28 (101)  2.41 ± 1.60 (101) Tmax (h)1.00 (101) 1.50 (101) [0.50-4.00] [0.50-6.00] AUC(0-t) (h*ng/mL)  3.53 ±1.87 (101)  3.99 ± 2.51 (101) AUC(inf) (h*ng/mL) 3.84 ± 1.80 (91) 4.05 ±2.50 (86) λz (h⁻¹) 0.1488 ± 0.0675 (91) 0.3271 ± 0.1555 (86) t½ (h) 5.58± 2.66 (91) 3.07 ± 2.64 (86) *Arithmetic mean ± standard deviation (N)except Tmax for which the median (N) [Range] is reported.

The time to peak mean dronabinol concentration for the Aqueous-basedOral Cannabinoid Solution of the present invention is shorter than thetime to peak mean dronabinol concentration for the Marinol® referenceproduct. The time to peak mean dronabinol concentration for theAqueous-based Oral Cannabinoid Solution ranged from about 0.50 hoursafter administration to about 4.00 hours after administration while thetime to peak mean dronabinol concentration for the Marinol® referenceproduct ranged from about 0.50 hours after administration to about 6.00hours after administration. With respect to THC levels, pharmacokineticparameters such as T_(max), C_(max), and AUC show less variability afterAqueous-based Oral Cannabinoid Solution administration compared to theMarinol® reference product. The systemic in vivo absorption of THC ismore consistent with the Aqueous-based Oral Cannabinoid Solution of thepresent invention than it is with the Marinol reference product. Thepeak mean dronabinol concentration for the Aqueous-based OralCannabinoid Solution of the present invention ranged from about 0.67ng/mL to about 3.23 ng/mL while the peak mean dronabinol concentrationfor the Marinol® reference product ranged from about 0.81 ng/mL to about4.01 ng/mL.

Results of the pharmacokinetic and statistical analyses for theAqueous-based Oral Cannabinoid Solution (A) of the present invention andthe Marinol® reference product is shown in Table 16. Table 16 shows thepharmacokinetic parameters of 11-OH-Δ9-THC, the primary and activemetabolite of dronabinol, comparing the Aqueous-based Oral CannabinoidSolution (Test A) of the present invention and the Marinol® referenceproduct.

TABLE 16 Summary of PK parameters for 11-OH-Δ9-THC with replicatescombined after oral administration of single 4.25 mg doses of DronabinolSolution and 5 mg dose of Marinol ® capsule to healthy volunteers underfasted conditions. Test Formulation (A) Marinol ® Parameter* (Test)(Reference) Cmax (ng/mL)  2.77 ± 1.48 (101)  3.63 ± 2.19 (101) Tmax (h)1.50 (101) 1.50 (101) [0.50-4.00] [0.50-6.00] AUC(0-t) (h*ng/mL)  10.6 ±5.13 (101)  12.9 ± 6.67 (101) AUC(inf) (h*ng/mL) 11.2 ± 5.33 (97) 13.8 ±6.88 (97) λz (h⁻¹) 0.0716 ± 0.0452 (97) 0.0708 ± 0.0583 (97) t½ (h) 11.7± 4.01 (97) 11.9 ± 3.89 (97) *Arithmetic mean ± standard deviation (N)except Tmax for which the median (N) [Range] is reported.

The time to peak mean 11-OH-Δ9-THC concentration for the Aqueous-basedOral Cannabinoid Solution of the present invention is equal to the timeto peak mean dronabinol concentration for the Marinol® referenceproduct. The time to peak mean dronabinol concentration for theAqueous-based Oral Cannabinoid Solution ranged from about 0.50 hoursafter administration to about 4.00 hours after administration while thetime to peak mean dronabinol concentration for the Marinol® referenceproduct ranged from about 0.50 hours after administration to about 6.00hours after administration. With respect to 11-OH-Δ9-THC levels,pharmacokinetic parameters such as Tmax, Cmax, and AUC show lessvariability after Aqueous-based Oral Cannabinoid Solution administrationcompared to the Marinol® reference product. The systemic in vivoabsorption of 11-OH-Δ9-THC is more consistent with the Aqueous-basedOral Cannabinoid Solution of the present invention than it is with theMarinol® reference product. The peak mean 11-OH-Δ9-THC concentration forthe Aqueous-based Oral Cannabinoid Solution of the present inventionranged from about 1.29 ng/mL to about 4.25 ng/mL while the peak meandronabinol concentration for the Marinol® reference product ranged fromabout 1.44 ng/mL to about 5.82 ng/mL.

Example 4 Dronabinol Oral Solution 4.25 mg Dose Versus 5 mg DronabinolCapsules

The dronabinol solution of example 1 was used in another bioavailabilitystudy. However, in this study, 0.85 mL of the solution was administeredto subjects equating to a 4.25 mg dose.

Pharmacokinetic and Bioavailability Analysis

Protocol was an open-label, 3-treatment, 3-period, 6-sequence,single-dose, randomized crossover study of the comparativebioavailability of the aqueous-based oral dronabinol solution of thepresent invention and Marinol® 5 mg Capsules (Unimed Pharmaceuticals)after fasted and fed conditions. Subjects received one dose of eachtreatment per period according the to the randomization schedule.Fifty-four (54) healthy male and female volunteers were randomlyassigned to 1 of 3 treatment sequences, Sequence 1 (T→R→T→R) or Sequence2 (R→T→R→T), where T=the test product, Dronabinol Solution, and R=thereference product, Marinol® capsules.

Fifty-four (54) subjects were enrolled into the study. One (1) subjectcompleted only the first period and no samples were analyzed. One (1)subject completed only the first 2 periods. The analysis population wastherefore comprised of 54 subjects, 52 of whom completed all 4treatments, 1 that completed 1 of the 4 treatments and 1 that completed2 of the 4 treatments.

Aqueous-Based Oral Cannabinoid Solution 5 mg/ml

Safety was assessed using the following parameters: physicalexaminations, vital signs, clinical laboratory evaluations, ECGs,concomitant medication assessments, and adverse event assessments. Inaddition, subjects were observed for a psychotic episode (e.g.hallucinations, paranoid delusions, personality changes, disorganizedthinking) and monitored until their mental status returned to normalwhile confined to the study site.

Statistical Methods

Data from 52 subjects who completed the study were included in thepharmacokinetic and statistical analyses.

The following pharmacokinetic parameters were calculated: peakconcentration in plasma (C_(max)), time to peak concentration (T_(max)),time prior to first measurable concentration (T_(lag)), lastquantifiable concentration determined directly from individualconcentration-time data (C_(last)), time of last quantifiableconcentration (T_(last)), elimination rate constant (λ_(z)), terminalhalf-life (T_(1/2)), area under the concentration-time curve fromtime-zero to the time of the last quantifiable concentration(AUC_(0-t)), area under the plasma concentration time curve fromtime-zero extrapolated to infinity (AUC_(inf)), percentage of AUC_(inf)obtained by extrapolation (AUC_(extrap)), calculated asAUC_(extrap)=[(AUC_(inf)−AUC_(0-t))/AUC_(inf)]*100, apparent oralclearance (CL/F), calculated as: CL/F=Dose/AUC_(inf) for dronabinolonly, and volume of distribution in the terminal elimination phase(Vz/F), calculated as Vz/F=(CL/F)/λZ for dronabinol only.

Results and Conclusions

Results of the pharmacokinetic and statistical analyses for theAqueous-based Oral Cannabinoid Solution (A) of the present invention andthe Marinol® reference product is shown in Table 17. Table 17 shows thepharmacokinetic parameters of dronabinol comparing the Aqueous-basedOral Cannabinoid Solution (Test A) of the present invention and theMarinol® reference product.

TABLE 17 Summary of PK parameters for dronabinol with replicatescombined after oral administration of single 4.25 mg doses of DronabinolSolution under fed conditions and 5 mg dose of Marinol ® Capsule underfed and fasted conditions to healthy volunteers. Test Formulation (A)Marinol ® Marinol ® Parameter* (Fed) (Fed) (Fasted) T_(lag) (h) 0.15 ±0.07 (52) 2.02 ± 1.42 (54) 0.52 ± 0.55 (53) T_(max)(h) 7.67 ± 3.43 (52)5.59 ± 3.24 (54) 1.73 ± 1.74 (53) C_(max) (ng/mL)  1.52 ± 0.969 (52) 2.6 ± 1.74 (54) 2.19 ± 1.06 (53) AUC_(0-t) (h*ng/mL) 9.103 ± 3.842 (52)10.47 ± 4.846 (54) 4.437 ± 2.67 (53)  AUC_(0-inf) (h*ng/mL) 10.25 ± 3.78(30)  12.21 ± 4.834 (35) 4.334 ± 2.493 (47) AUC_(extrap) (%) 3.97 ± 2(30)   3.68 ± 2.54 (35) 4.66 ± 2.76 (47) λz (h⁻¹) 0.1168 ± 0.0705 (30)0.1432 ± 0.1077 (35)  0.292 ± 0.1663 (47) t½ (h) 9.35 ± 6.73 (30) 10.41± 9.24 (35)  4.82 ± 5.85 (47) T_(last) (h) 30.08 ± 9.91 (52)  28.59 ±11.3 (54)  15.55 ± 10 (53)   C_(last) (ng/mL) 0.0366 ± 0.0141 (52)0.0392 ± 0.0202 (54) 0.0362 ± 0.0111 (53) CL/F (L/h) 485.9 ± 235.1 (30)491.1 ± 236.3 (35)  1521 ± 794.4 (47) Vz/F (L) 5457 ± 3096 (30) 5727 ±4585 (35) 7129 ± 5190 (47) *Arithmetic mean ± standard deviation (n)denotes the number of subjects measured.

The mean time to first measurable dronabinol concentration is shorterfor the Aqueous-based Oral Cannabinoid Solution of the present invention(“Formulation A”) than the mean time to first measurable concentrationfor Marinol® reference product. Additionally, the variation in mean timeto first measurable dronabinol concentration is less for Formulation Athan the variation in mean time to first measurable concentration forMarinol®. Formulation A achieved a first measurable concentration in0.15 hours under fed conditions whereas Marinol® achieved a firstmeasurable concentration in 2.02 hours under fed conditions and 0.52hours under fasting conditions. With respect to THC levels,pharmacokinetic parameters such as C_(max), and AUC show lessvariability under fed conditions after Formulation A administrationcompared to Marinol®. The systemic in vivo absorption of THC is moreconsistent with Formulation A than it is with the Marinol® referenceproduct. The peak mean dronabinol concentration for Formulation A rangedfrom about 0.55 ng/mL to about 2.49 ng/mL while the peak mean dronabinolconcentration for Marinol® ranged from about 0.86 ng/mL to about 4.34ng/mL.

TABLE 18 Summary of AUC for dronabinol with replicates combined afteroral administration of single 4.25 mg doses of Dronabinol Solution underfed conditions and 5 mg dose of Marinol ® Capsule under fed and fastedconditions to healthy volunteers. Test Formulation (A) Marinol ®Marinol ® Parameter* (Fed) (Fed) (Fasted) AUC_(0-0.08) (h*ng/mL)5.465E−5 ± 0.000276  0 0 AUC_(0-0.17) (h*ng/mL) 0.001436 ± 0.002674 4.651E-7 ± 2.293E−6 0.001147 ± 0.005643 AUC_(0-0.25) (h*ng/mL) 0.005287± 0.007754 0.0003389 ± 0.001466  0.007954 ± 0.02751  AUC_(0-0.5)(h*ng/mL) 0.03156 ± 0.03071 0.04463 ± 0.1429  0.1258 ± 0.2181AUC_(0-0.75) (h*ng/mL) 0.07568 ± 0.06561 0.1689 ± 0.4904 0.3632 ± 0.5013AUC₀₋₁ (h*ng/mL) 0.1316 ± 0.1105 0.3344 ± 0.9074 0.6404 ± 0.7613AUC_(0-1.5) (h*ng/mL) 0.2688 ± 0.2113 0.667 ± 1.692  1.19 ± 1.141 AUC₀₋₂(h*ng/mL) 0.4431 ± 0.3304 0.984 ± 2.308 1.726 ± 1.38  AUC_(0-2.5)(h*ng/mL) 0.6561 ± 0.5001 1.278 ± 2.704 2.216 ± 1.552 AUC₀₋₃ (h*ng/mL)0.8888 ± 0.6901 1.623 ± 2.971 2.596 ± 1.697 AUC_(0-3.5) (h*ng/mL)  1.126± 0.8562 2.056 ± 3.236 2.887 ± 1.802 AUC₀₋₄ (h*ng/mL) 1.392 ± 1.0462.531 ± 3.461 3.133 ± 1.866 *Arithmetic mean ± standard deviation.Number of subjects tested (“n”) for Test formulation A was 52, n forMarinol ® fed is 54 and n for Marinol ® fasted is 53.

Administration of Formulation A under fed conditions resulted in ameasurable AUC twice as fast as administration of Marinol® under fedconditions. Specifically, administration of Formulation A achieved ameasurable AUC within 0.08 hours or about 5 minutes whereas Marinol®under fed conditions achieved a smaller yet measurable AUC at 0.17 hoursor about 10 minutes. Further, Formulation A maintained a larger AUC thanMarinol® under fed conditions for the first 15 minutes afteradministration.

Additionally, administration of Formulation A under fed conditionsresulted in less variability than Marinol® under fed or fastingconditions at all time points. For example, administration ofFormulation A under fed conditions achieved an AUC₀₋₂ (h*ng/mL) range ofabout 0.11 to about 0.77 whereas Marinol® achieved a range of about−1.32 to about 3.29 under fed conditions and about 0.35 to about 3.1.

Results of the pharmacokinetic and statistical analyses for FormulationA of the present invention and the Marinol® reference product is shownin Table 19. Table 19 shows the pharmacokinetic parameters of11-OH-Δ9-THC, the primary and active metabolite of dronabinol, comparingFormulation A and Marinol®.

TABLE 19 Summary of PK parameters for 11-OH-Δ9-THC with replicatescombined after oral administration of single 4.25 mg doses of DronabinolSolution under fed conditions and 5 mg dose of Marinol ® Capsule underfed and fasted conditions to healthy volunteers. Test Formulation (A)Marinol ® Marinol ® Parameter* (Fed) (Fed) (Fasted) T_(lag) (h) 0.2 ±0.1 1.91 ± 1.29 0.55 ± 0.56 T_(max)(h) 8.5 ± 3.5 5.95 ± 3.35 1.91 ± 1.15C_(max) (ng/mL)  1.23 ± 0.602 2.16 ± 1.5  3.12 ± 1.67 AUC_(0-t)(h*ng/mL) 12.61 ± 5.099 14.84 ± 6.485 11.17 ± 6.068 AU_(0-inf) (h*ng/mL)13.29 ± 5.235 15.59 ± 6.667 11.81 ± 6.175 AUC_(extrap) (%)  5.4 ± 2.044.87 ± 1.77 6.33 ± 3.62 λz (h⁻¹)  0.068 ± 0.0278 0.0683 ± 0.0247 0.0669± 0.0475 t½ (h) 11.23 ± 2.97  11.11 ± 2.97  12.47 ± 4.26  T_(last) (h)44.24 ± 7.53    44 ± 6.59 37.82 ± 9.81  C_(last) (ng/mL) 0.0415 ± 0.0121 0.045 ± 0.0152  0.0357 ± 0.00893 *Arithmetic mean ± standard deviation.Number of subjects tested (“n”) for Test formulation A was 52, n forMarinol ® fed is 54 and n for Marinol ® fasted is 53.

The mean time to first measurable 11-OH-Δ9-THC concentration is shorterfor Formulation A than the mean time to first measurable concentrationfor Marinol® reference product. Additionally, the variation in mean timeto first measurable 11-OH-Δ9-THC concentration is less for Formulation Athan the variation in mean time to first measurable concentration forMarinol®. Formulation A achieved a first measurable concentration in 0.2hours under fed conditions whereas Marinol® achieved a first measurableconcentration in 1.91 hours under fed conditions and 0.55 hours underfasting conditions. With respect to THC levels, pharmacokineticparameters such as Cmax, and AUC show less variability under fedconditions after Formulation A administration compared to Marinol®. Thesystemic in vivo absorption of THC is more consistent with Formulation Athan it is with the Marinol® reference product. The peak mean11-OH-Δ9-THC concentration for Formulation A ranged from about 0.63ng/mL to about 1.83 ng/mL while the peak mean dronabinol concentrationfor Marinol® ranged from about 0.67 ng/mL to about 3.66 ng/mL.

TABLE 20 Summary of AUC for 11-OH-Δ9-THC with replicates combined afteroral administration of single 4.25 mg doses of Dronabinol Solution underfed conditions and 5 mg dose of Marinol ® Capsule under fed and fastedconditions to healthy volunteers. Test Formulation (A) Marinol ®Marinol ® Parameter* (Fed) (Fed) (Fasted) AUC_(0-0.08) (h*ng/mL) 0 0 0AUC_(0-0.17) (h*ng/mL) 0.001018 ± 0.002015 2.814E−7 ± 1.312E−6 0.0003438± 0.0021   AUC_(0-0.25) (h*ng/mL) 0.004927 ± 0.008388 0.0002075 ±0.0008453 0.002878 ± 0.0111  AUC_(0-0.5) (h*ng/mL)  0.0386 ± 0.049310.02705 ± 0.08847 0.09368 ± 0.1622  AUC_(0-0.75) (h*ng/mL) 0.09513 ±0.1044  0.1105 ± 0.3228 0.3418 ± 0.4711 AUC₀₋₁ (h*ng/mL) 0.1639 ± 0.16190.2424 ± 0.6559 0.7084 ± 0.8221 AUC_(0-1.5) (h*ng/mL) 0.3225 ± 0.27990.5393 ± 1.368  1.651 ± 1.484 AUC₀₋₂ (h*ng/mL)  0.512 ± 0.4116 0.8421 ±1.985  2.723 ± 2.081 AUC_(0-2.5) (h*ng/mL) 0.7313 ± 0.5675 1.154 ± 2.4673.745 ± 2.561 AUC₀₋₃ (h*ng/mL) 0.9681 ± 0.7343 1.506 ± 2.821 4.601 ±2.94  AUC_(0-3.5) (h*ng/mL)  1.22 ± 0.9066 1.929 ± 3.125 5.271 ± 3.221AUC₀₋₄ (h*ng/mL)  1.5 ± 1.091 2.421 ± 3.436 5.817 ± 3.43  *Arithmeticmean ± standard deviation. Number of subjects tested (“n”) for Testformulation A was 52, n for Marinol ® fed is 54 and n for Marinol ®fasted is 53.

Administration of Formulation A under fed conditions resulted in lessvariability than Marinol® in AUC of 11-OH-Δ9-THC under fed or fastingconditions at all time points. For example, administration ofFormulation A under fed conditions achieved an AUC₀₋₂ (h*ng/mL) range ofabout 0.10 to about 0.92 whereas Marinol® achieved a range of about−1.14 to about 2.82 under fed conditions and about 0.64 to about 4.80.

Example 5 Dronabinol Stability

The following stability studies were conducted to determine thelong-term storage stability of dronabinol in hydro-alcohol formulationscontaining 33% or less water. Dronabinol formulations, as detailed inTable 21, below, were individually filled into separate glass vials andsubjected to accelerated storage conditions at 55° C.±2° C. Samples ofeach vial were taken at 4 weeks. These samples were analyzed for totalimpurity levels. Impurity levels were detected using high-performanceliquid chromatography with an ultraviolet detector. Impurity analysiswas performed at 228 nm and expressed as a % area.

TABLE 21 Zero time 1M/55° C./75% RH Total Total Dronabinol EthanolPG/PEG Water Potency impurities Potency impurities ID # (%) (%) (%) (%)% (%) % (%) EN1197071 0.5 81.9 17.5 0 99.03 1.67 96.70 3.38 EN11970730.5 71.9 17.5 10 98.37 1.67 97.36 2.53 RW1182130 0.5 61.9 17.5 20 98.611.68 98.04 2.81 RW1182131 0.5 50 17.5 31.9 99.17 1.68 98.07 3.23RW1182132 0.5 48.9 17.5 33 98.07 1.69 96.9 3.25As seen in the Table 21, above, Dronabinol formulations containing 33%or less water are stable at accelerated storage conditions. Each ofthese formulations provide a total impurity level that is significantlybelow the USP-Dronabinol monograph level of 5.0%.Dronabinol solutions containing 0.05-20 mg/mL dronabinol, alcohol, 33%or less water and 5-21% of a cosolvent consisting of propylene glycol,polyethylene glycol or a combination thereof may not form proper dropletsizes necessary to be transformed into a mist by nebulizers currentlyavailable on the market

1-3. (canceled)
 4. A method of treating a disorder selected from thegroup consisting of nausea, vomiting, anorexia, cachexia, pain,gastrointestinal tract distress, heartburn, indigestion, stomachache,sour stomach, inflammatory bowel disease, Crohn's disease, gastritis,irritable bowel syndrome, ulcerative colitis, migraine headaches, spinalcord injury, anxiety, postmenstrual syndrome, Alzheimer's dementia,agitation, muscle spasms and other involuntary movement disorders,Parkinson's disease and Parkinsonian-type symptoms, spasticity as resultof multiple sclerosis, glaucoma, neuropathic pain, anxiety disorders,cancer cachexia, dystonia, Huntington's disease, Tourette's syndrome,epilepsy, and appetite stimulation in Alzheimer's disease comprising:administration of a stable oral dronabinol solution to a subject in needthereof comprising from about 0.1% to about 5% w/w of dronabinol, 31.90%or less water, from about 15% to about 90% w/w alcohol and from about17.5% w/w of a co-solvent consisting of propylene glycol, polyethyleneglycol or a mixture thereof, and an antioxidant, wherein w/w denotesweight by total weight of the solution, and wherein the pharmaceuticalformulation solution is an oral solution.
 5. The method of claim 4,wherein the stable oral dronabinol solution is administered orally, orvia nasogastric, intramuscular, direct absorption through mucousmembrane tissues, pulmonary, intravenous, transdermal, ophthalmic,vaginal, rectal, parenteral or transmucosal routes.
 6. The method ofclaim 5, wherein the stable oral dronabinol solution is administeredorally via the buccal or sublingual route.
 7. The method of claim 1,wherein the stable oral dronabinol solution is administered incombination with a cannabinoid, Cannabis-derived molecule or othermedication.
 8. The method of claim 7, wherein the other medication isselected from the group consisting of antiemetics, nonsteroidalanti-inflammatory agents, non-narcotic analgesics and steroids.
 9. Themethod of claim 7, wherein the cannabinoid, Cannabis-derived molecule orother medication is administered simultaneously, substantiallysimultaneously, or sequentially with the stable oral dronabinolsolution.
 10. The method of claim 1, wherein the stable oral dronabinolsolution is administered to the subject in need thereof at a therapeuticdose.
 11. The method of claim 1, wherein the stable oral dronabinolsolution is converted to a suspension, emulsion, suppository, spray,aerosol, gel, drops, syrup, elixir, or other dosage form.